The present invention relates to a class of substituted (R)-3-(1-phenylethyl)-3H-imidazole-4-carboxylic acid esters which interact selectively with the mitochondrial cytochrome P-450 species in the adrenal cortex (Vanden Bossche, 1984). When labelled with radiohalogen (iodine-123; bromine-76; fluorine-18 and others) these compounds serve as radiotracers for the diagnosis of adrenal cortical masses such as incidentalomas, adenomas, primary and metastatic cortical carcinoma. When labelled with a betaemitting radionuclide (iodine-131; bromine-82), these radiotracers may be used for radionuclide therapy. The main application is for tumour diagnosis (Khan 2003).
In particular, the compounds according to this invention are potent inhibitors of steroid P450, β-hydroxylation and bind with high affinity to adrenocortical membranes. In fact, the compounds in accordance with this invention have been found to vossess an almost 1000-fold selective affinity when compared with known, clinically used inhibitors (metyrapone, ketoconazole). Therefore, when injected intravenously, the labelled derivatives of the present invention accumulate rapidly in the adrenals, reaching radioactivity levels that are diagnostically useful.
The parent compounds metomidate and etomidate (methyl and ethyl ester; MTO and ETO respectively) are clinically used as a short-acting hypnotic drug. When incubated with human adrenocortical tissue slices, it was shown to block the conversion of 11-deoxycortisol to cortisol and of 11-deoxycorticosterone (DOC) to corticosterone and aldosterone (Weber 1993; Engelhardt 1994). Also metomidate (MTO), the methyl ester, is an equally potent inhibitor of steroid 110-hydroxylation. (R)-configuration of the methyl substituent at the chiral C-atom is essential for enzyme inhibition (Vanden Bossche, 1984).
Clinical findings with the radiotracer [O-methyl-11C]metomidate have indicated high uptake in lesions of adrenocortical origin, including adenomas, but very low uptake in lesions of non-adrenocortical origin (Bergstrom 1998; 2000). Specific uptake has been reported in multiple metastases in the lung of a primary adrenocortical carcinoma (Mitterhauser 2002). However, the differentiation between benign (e.g., adenoma) and malignant (e.g., carcinoma) is primarily based on the size and shape of the lesion; irregularities in tumour uptake and multiple lesions are an indication of malignancy (Khan 2003).
Although 11C-metomidate has “ideal” biological characteristics for scintigraphy of the adrenals and tumor derived therefrom, application of the radiopharmaceutical is limited to hospitals with a PET facility. 11C is a cyclotron product and decays with a half-life of 20 min, therefore, 11C-metomidate must be synthesized immediately prior to use.
Halogenations, on the other hand, offer sufficient flexibility, time for preparation and shipment. (Iodine-123 T1/2=13.2 hours; Br-76 T1/2=16 hours).
Enzyme inhibitors, such as metyrapone have been labelled with radioiodine for adrenal scintigraphy, however, these compounds have never been used for clinical diagnosis (Wieland, 1982; Robien & Zolle, 1983). A comparison of the binding affinities (IC50-values) of known inhibitors with etomidate clearly demonstrated the higher potency of etomidate and metomidate.
The available radiotracers for imaging the adrenal cortex and adrenal cortex-derived tumors are labelled cholesterol derivatives. These include 6,β[131I]-iodomethyl-19-norcholesterol (NP-59) (Basmadjian, 1975) and 6β-[75Se]-selenomethyl-1 g-norcholesterol (Scintadren™) (Sakar, 1976). Both NP-59 and Scintadren™ accumulate in the adrenals slowly, within days, requiring long-lived radionuclides as a label (Iodine-131 T1/2=8.04 days; Selen-75 T1/2=−120 days). Iodine-131 is also emitting beta-radiation, which contributes considerably to the radiation exposure. The diagnostic use of beta-emitters is no longer state of the art.
In view of the drawbacks of above mentioned agents with respect to patient care (high radiation exposure, repeated imaging procedures), the development of radiolabeled derivatives of etomidate and metomidate would greatly improve radionuclide imaging procedures for the detection and follow-up of adrenal disease.
In a previous study of [18F]FETO, (the [18F]fluoroethyl ester of etomidate, (R)-1-(1-phenylethyl)-1Himidazole-5-carboxylic acid, 20-[18F]fluoroethyl ester), an analogue of [11C]MTO and [11C]ETO was prepared in the following two step procedure: First, [18F]fluoride was reacted with 2-bromoethyl triflate using the kyptofix/acetonitrile method to yield 2-bromo-[18F]fluoroethane ([18F]BFE). In the second step, [18F]BFE was reacted with the tetrabutylaimmonium salt of (R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid to yield [18F]FETO. The overall synthesis time was about 80 min (Wadsak & Mitterhauser 2003).
It is desirable to develop an improved one-step 18F fluorination synthetic methodology which would provide a shorter reaction time (which means faster synthesis of 18F-labelled compound for production, a higher yield by avoiding side reactions, higher reproducibility and can be easily automated.
A compound thus developed can be used as a radiopharmaceutical to diagnose adrenal cortical masses such as incidentaloma, adenoma, primary and metastatic cortical carcinoma, and have further applications in therapy monitoring.
Discussion or citation of a reference herein shall not be construed as an admission that such reference is prior art to the present invention.